Proteins and peptides have become powerful therapeutic agents in the treatment of various diseases, such as cancer, inflammatory, cardiovascular, respiratory, and infectious diseases. However, formulation and delivery of these molecules are challenging due to solubility and viscosity limitations. Except for highly potent molecules, formulations of these molecules need to contain relatively high concentrations of the protein to enable efficacious dose levels by subcutaneous (“SC”) or intramuscular (“IM”) routes of administration.
Commercialization strategies often involve lyophilized formulations that require reconstitution of the protein prior to being delivered by injection, which can add costs and time to the manufacturing process. Ready-to-use solution formulations of proteins and peptides, when feasible, can minimize this inconvenience. However, the requirement for a high concentration of the protein adds complexity to formulation design and promotes instability.
It has been estimated that greater than 20% of all biopharmaceuticals currently being evaluated in clinical trials are monoclonal antibodies (“mAbs”). In general, mAb therapies require the delivery of between approximately 100 mg and approximately 1 g of protein per dose. Because the high end of formulation concentrations for mAbs is typically in the range of 50 mg/ml, such treatments commonly require the administration of 2 to 20 ml. Typically, such volumes are administered only through intravenous (“IV”) infusion performed in a clinical or hospital setting, which leads to poor patient compliance.
To achieve a high protein concentration, nonaqueous suspensions of proteins have been formulated. In these formulations, the protein is suspended in a vehicle that includes at least two of the following: a polymer, a surfactant, and a solvent. The formulation has a protein concentration of up to 500 mg/ml.
To expand therapeutic opportunities and increase patient compliance, a method of achieving a high concentration of mAbs is needed so that large protein doses are deliverable in a small volume appropriate for SC or IM injection. One possible approach is to prepare extremely high concentration preparations of soluble mAbs, on the order of 150 to 250 mg/ml. However, achieving such highly concentrated mAb solutions is problematic due to solubility limitations and/or relatively high viscosities, which often results in protein aggregation and poor overall stability.
Polyethoxylated castor oil (also known as polyoxyl castor oil, polyoxyl 35 castor oil, polyoxyethylated castor oil, macrogolglycerol ricinoleate, or macrogolglyceroli ricinoleas) has been used as a solvent for pharmaceutical compositions that include a hydrophobic drug, such as miconazole, echinomycin, teniposide, diazepam, althesin, or paclitaxel. The hydrophobic drug and the polyethoxylated castor oil form a solution. To further solubilize the hydrophobic drug, many of these pharmaceutical compositions also include an alcohol.
There remains a need to develop highly concentrated protein formulations to enable delivery of a variety of therapeutic proteins in a convenient way with a small volume.